Hepatitis C is an infectious
liver disease caused by the hepatitis C virus (HCV). The virus, which causes
inflammation in the liver and can lead to more serious illness, primarily
is spread by intravenous contact with the blood of an infected person. About
4 million people in the United States have been infected, making it the Nation’s
most common blood–borne disease, resulting in the deaths of between
10,000 and 12,000 people each year (National Institute of Diabetes and Digestive
and Kidney Diseases 2003). Those at heightened risk for HCV infection include
intravenous drug users, people who received blood transfusions or organ transplants
before 1992 or clotting factors made before 1987, health care workers who
suffer needle–stick accidents, and infants born to mothers who are infected
with HCV (Centers for Disease Control and Prevention 1998). Several factors
may accelerate the progression of hepatitis C, including older age at the
time of infection, male gender, obesity, abnormal accumulation of fat in the
liver (a condition known as fatty liver, or steatosis), and excessive alcohol
consumption (Poynard et al. 2001).

This article discusses
the mechanisms by which alcohol may exacerbate HCV–infected patients’
risk of disease progression, reviews issues in the treatment of alcoholic
patients with HCV infection, and addresses important areas of future research.

Epidemiology of Hepatitis
C Among Alcoholics

Almost one–third
of alcoholics with clinical symptoms of liver disease have been infected with
HCV, which is four times the rate of HCV infection found in alcoholics who
do not have liver disease (Coelho–Little et al. 1995; Mendenhall et
al. 1991; Takase et al. 1993). As shown in figure 1, people with more severe
liver disease are considerably more likely to test positive for HCV infection
than those with less severe liver disease (Takase et al. 1993).

Levels of Alcohol Consumption
in HCV Patients and the Risk of Further Liver Disease

Several studies have indicated
that heavy alcohol consumption accelerates patients’ progression from
chronic HCV to cirrhosis (a condition in which fibrous scar tissue replaces
healthy liver tissue), and liver cancer (specifically, hepatocellular carcinoma,
the most common form of liver cancer). Although fewer studies have examined
the effects of moderate drinking on the course of liver disease in HCV patients,
there is some indication that alcohol consumption in the moderate–to–heavy
range may increase HCV–infected patients’ risk of developing liver
fibrosis and cirrhosis. Research on whether gender has any effect on alcohol
consumption and liver disease progression in HCV patients is very limited.

Cirrhosis

In a study of 2,235 HCV–infected
patients, Poynard and colleagues (1997) observed that patients who drank heavily
(more than 50 grams [g] of alcohol, or 4.2 drinks, per day1) (1
The National Institute on Alcohol Abuse and Alcoholism [NIAAA] defines a standard
drink as 11–14 g of alcohol. This corresponds to approximately one shot
of 80–proof alcohol [about 14 g alcohol], one glass of wine [11 g],
or one 12–oz. beer [12.8 g].) tended to show much more advanced liver
scarring (i.e., fibrosis, a defining feature of cirrhosis) than those who
did not drink as heavily. In addition, the researchers identified a group
of “rapid fibrosers,” who were more likely to be male, heavy drinkers,
and infected with HCV after age 40.

Wiley and colleagues (1998)
observed that HCV–infected patients who drank heavily were significantly
more likely to develop cirrhosis than those who were not heavy drinkers. In
addition, among patients who did develop cirrhosis, the disease emerged considerably
sooner for patients who drank heavily than for those who did not (see figure
2).

Figure 2
Relationship between fibrosis severity (grades 1–4) and years
of HCV infection. Patients who reported significant alcohol consumption
(more than 40 g of alcohol per day, or 3.3 drinks, for women; and more
than 60 g of alcohol per day, or about 5 drinks, for men) experienced
markedly faster disease progression than patients who did not report
significant alcohol intake.

SOURCE: Wiley et
al. 1998.

Bellentani and colleagues
(1999) analyzed hepatitis virus markers (including the virus’s genetic
material, HCV RNA, and antibodies to the virus), alcohol intake, and clinical
and biochemical evidence of liver disease in a random sample of 6,917 people
in northern Italy. Regardless of HCV status, subjects who were heavy drinkers
(which the authors defined as drinking more than 30 g, or 2.5 drinks, per
day) for more than 10 years were three times as likely to have cirrhosis than
those who were not heavy drinkers. Among HCV–positive subjects, 32 percent
of those who were heavy drinkers had cirrhosis, compared with 10 percent of
those who were not heavy drinkers. There were five cases of hepatocellular
carcinoma, all in the heavier drinking group.

Seeff and colleagues (2001)
studied 1,030 patients who had been enrolled in a prospective investigation
of transfusion–associated HCV conducted in the United States between
1968 and 1980. In a followup investigation conducted an average of 15 years
after transfusions had occurred, the researchers found that 17 percent of
patients infected with transfusion–associated HCV had developed cirrhosis,
compared with 3.2 percent of patients with transfusion–associated non–A,
non–B, and non–C hepatitis, and 2.8 percent of uninfected patients.
Alcohol use greatly exacerbated patients’ risk of progression from chronic
hepatitis to cirrhosis. Patients with both transfusion–associated HCV
and a history of heavy alcohol use were 31 times more likely to develop cirrhosis
than control subjects without a history of alcohol abuse.

Perhaps the most dramatic
demonstration that alcohol multiplies HCV–infected patients’ risk
of cirrhosis came from a study by Corrao and Arico (1998). Of 285 cirrhotic
subjects, only 1.4 percent (4 subjects) were HCV–positive and nondrinkers,
compared with 11.2 percent (32 subjects) who were both HCV–positive
and heavy drinkers.

People infected with both
HCV and HIV are more likely to develop cirrhosis than are patients who are
infected only with HCV, and alcoholism further potentiates this mechanism
(Di Martino et al. 2001).

Liver Cancer

An Italian survey showed
that alcohol intake doubles the risk of hepatocellular carcinoma in HCV–infected
patients who drink 41 to 80 g of alcohol per day (between 3.4 and 6.7 drinks)
and quadruples the risk for patients who drink more than 80 g of alcohol per
day (Donato et al. 2002). Other research has shown that HCV–infected
patients who drink heavily are more likely to develop liver cancer at a younger
age than are those who drink less. For example, Noda and colleagues (1996)
observed that patients who drank at least 46 g of alcohol (3.8 drinks) daily
were diagnosed with hepatocellular carcinoma an average of 26 years after
developing transfusion–associated HCV, whereas those who drank less
than 46 g per day were diagnosed with cancer an average of 31 years after
transfusion. And Kubo and colleagues (1997) found that, among HCV–infected
patients with hepatocellular carcinoma, heavy drinkers had more advanced tumors
and died sooner after diagnosis than did nondrinkers.

Moderate–to–Heavy
Drinking and Disease Progression

Most studies have evaluated
the effect of extremely heavy drinking on the progression of HCV infection
to other liver disease, with little emphasis on the effects of moderate drinking
on disease progression. However, some studies have found indications that
moderate–to–heavy alcohol consumption also may increase the risk
of developing liver fibrosis and cirrhosis in patients infected with HCV.

Ostapowicz and colleagues
(1998) specified no particular threshold level above which the risk of disease
progression increases but found that, among patients with chronic HCV infection,
those who had cirrhosis reported higher lifetime and total alcohol consumption
than those HCV patients who did not have cirrhosis.

Several other studies
have examined the effects of moderate drinking on HCV progression.2
(2 In these studies, definitions of moderate drinking differ from
current Federal guidelines, which consider moderate drinking to be no more
than one drink per day for women, and no more than two drinks per day for
men [U.S. Department of Agriculture and the U.S. Department of Health and
Human Services 1995].) Assessing HCV–infected patients who drank less
than 40 g of alcohol (3.3 drinks) per day, Westin and colleagues (2002) found
that patients whose alcohol intake was above the median level (4.8 g of alcohol,
or less than one drink per day) showed more liver scarring (fibrosis) than
patients whose alcohol consumption was below the median level. Hézode
and colleagues (2003) also found that the severity of fibrosis in patients
with chronic HCV was correlated with the amount of alcohol consumed (see figure
3). Finally, a recent study of 180 patients with untreated chronic hepatitis
C confirmed these findings (Zarski et al. 2003).

Figure 3
Alcohol consumption and liver fibrosis in patients with chronic HCV.
More advanced fibrosis (stages 2 through 4) was observed in 29 percent
of patients who reported no alcohol intake, 34.4 percent of those who
had minimal intake, 38.2 percent of those who had mild intake, and 67.6
percent of those who were moderate drinkers. Correspondingly, the incidence
of less advanced fibrosis (stages 0 through 1) decreased with increasing
alcohol consumption.

SOURCE: Hézode
et al. 2003.

Gender and
Disease Progression

The data regarding the
contribution of gender to the progression of HCV in alcoholics is quite limited.
Chronic hepatitis C often is milder in women than in men, but women may be
more sensitive than men to the adverse effects of alcohol (Becker et al. 1996).

Histologic Features of
Chronic Hepatitis C in Alcoholic Patients

As discussed above, there
is strong evidence that heavy alcohol consumption—and perhaps even moderate
consumption—increases the risk that HCV infection will progress to more
serious liver disease. In patients infected with HCV, alcohol consumption
has a direct effect on liver histology. Specifically, patients with HCV who
are drinkers show greater liver necrosis, inflammation, fibrosis, and fatty
infiltration than HCV patients who do not drink. Further, alcohol consumption
and fatty liver have been shown to act together to increase fibrosis in patients
infected with HCV, especially in those who are obese and diabetic (Monto et
al. 2002).

Mechanisms of Liver Injury
in Alcoholic Hepatitis C Infection

Although researchers do
not fully understand how alcohol consumption accelerates liver injury in patients
with HCV infection, it is likely that several factors are involved. The following
mechanisms have been proposed:

Increased replication
of HCV in the liver. As illustrated in figure 4, some research (although
not all) has found that greater alcohol consumption is related to higher
HCV RNA blood concentrations (Pessione et al. 1998). Moreover, as shown
in figure 5, when people infected with HCV who drank more than 10 g of
alcohol (about 5.8 drinks) per day abstained from alcohol or substantially
reduced their consumption for 4 months before treatment, HCV RNA levels
dropped; the decline in serum HCV RNA among subjects who drank less than
or equal to 10 g of alcohol (less than one drink) per day before abstaining
was not statistically significant (Cromie et al. 1996).

Figure
5 Reversibility of the increase in blood HCV RNA levels following
a 4–month alcohol–free diet. Group 1 consisted of subjects
who drank less than or equal to 10 grams (g) of alcohol per day when
the study began; subjects in Group 2 consumed 10 g of alcohol or more
per day at the outset of the study.

SOURCE: Cromie
et al. 1996.

Mutations of the HCV
virus (forming what are known as quasi–species). Alcoholics infected
with HCV show greater quasi–species complexity than do nonalcoholics
with HCV infection. In alcoholic HCV patients, such increased viral complexity
might make it difficult for the immune system to control the mutated viruses,
leading to progressive injury (Takahashi et al. 2001).

Increased programmed
cell death (apoptosis) of liver cells. Apoptotic death of liver cells,
which can ultimately lead to liver fibrosis, is increased by alcohol consumption
in people with HCV infection (Szabo 2003).

Higher levels of inflammation
and immunoregulatory proteins (specifically, interleukin, tumor necrosis
factor, and interferon). In research with mice, Geissler and colleagues
(1997) noted that chronic alcohol feeding in mice inhibited immune responses
(specifically, responses by T–helper cells and cytotoxic T–lymphocytes)
that play a pivotal role in removal of HCV from the body (i.e., HCV clearance).

Viral gene mutations.

Fatty liver. Accumulation
of fat in the liver is common in patients with HCV. Examining a large
group of patients with HCV infection, Serfaty and colleagues (2002) found
that fibrosis progressed about twice as quickly among drinkers with steatosis
as among drinkers without steatosis or nondrinkers with or without steatosis.

Oxidative stress.
Alcohol stimulates the production of reactive oxygen–containing
molecules (i.e., oxygen radicals). Heavy alcohol use also depletes the
body’s supply of molecules that normally defend tissues against
damage caused by oxygen radicals (i.e., antioxidants). This state, known
as oxidative stress, may accelerate liver damage in patients with HCV
(Rigamonti et al. 2003). (For more information about how alcohol use can
lead to oxidative stress and subsequent liver injury, see the article
by Nanji and French in the next issue of Alcohol Research & Health,
[Vol. 27, No. 4].)

Depression of the
immune system by alcohol.

Treatment Issues

Heavy alcohol use can
be detrimental to HCV–infected patients’ long–term response
to interferon therapy (see the sidebar for discussion of interferon treatment
for HCV). It is likely that alcohol affects HCV treatment effectiveness both
because drinking tends to interfere with patients’ adherence to therapy
and because alcohol interferes with interferon therapy’s antiviral actions.

The symptoms and
course of hepatitis C vary greatly. Many people who are infected with
the virus show no symptoms (although they can still infect others),
whereas some people may experience fatigue, weakness, fever, nausea,
abdominal pain, poor appetite, muscle and joint pain, or yellowing of
the skin and eyes (jaundice) (National Institutes of Health 2002). About
75 percent of patients who are infected with HCV develop chronic infection
(Centers for Disease Control and Prevention 1998). Between 10 and 40
percent of HCV patients develop cirrhosis (a condition in which normal
liver cells are replaced by scar tissue) within 20 to 40 years, and
1 to 3 percent develop liver cancer.

Many patients who
develop cirrhosis show no symptoms of the disease and can expect long–term
survival (Di Bisceglie 2000). Data from a cohort of European patients
with cirrhosis followed for an average of 5 years showed that only 7
percent developed hepatocellular carcinoma, and 18 percent experienced
symptomatic liver failure (Fattovich et al. 1997). There currently is
no vaccine for hepatitis C.

Testing
and Treatment

Blood tests can
diagnose HCV infection, either by detecting antibodies to the virus
or by detecting the presence and quantity of the virus’s genetic
material (HCV RNA) itself (National Institutes of Health 2002). Liver
biopsy is quite helpful for evaluating the disease’s severity
prior to initiating treatment. Liver enzymes have little value in predicting
fibrosis.

There are six known
genetic variants (genotypes) of HCV, which vary geographically in their
rate of occurrence. Genotypes 1 (which accounts for 70 to 75 percent
of cases), 2, and 3 constitute the majority of genotypes in the United
States.

The standard treatment
for symptomatic hepatitis C infection is a combination of the drugs
pegylated interferon (peginterferon) and ribavirin (National Institutes
of Health 2002). Strict abstinence from alcohol is important during
treatment.

Currently, the best
indicator of effective treatment is a sustained virological response
(SVR), defined by the absence of detectable virus 24 weeks after the
end of treatment. Early viral response (a minimum 2 log decrease in
viral load during the first 12 weeks of treatment) is predictive of
SVR, and patients who fail to achieve an early viral response at week
12 should discontinue the treatment. Genotype 1 requires 1 year of treatment,
whereas genotypes 2 and 3 require a 6–month course. In research
with patients who did not consume alcohol during the therapy, SVR rates
of 42 to 46 percent for genotype 1 and 76 to 82 percent for genotypes
2 and 3 have been obtained (Di Bisceglie and Hoofnagle 2002).

—Eugene
R. Schiff and Nuri Ozden

References

Centers for Disease
Control and Prevention. Recommendations for prevention and control of
hepatitis C virus (HCV) infection and HCV–related chronic disease.
Morbidity and Mortality Weekly Reports 47:1–39, 1998.

Some research has indicated
that heavy drinkers who abstain from alcohol before interferon treatment respond
better to treatment than do those who continue to drink. In one study, heavy
drinkers who did not abstain from drinking before interferon treatment showed
a total lack of HCV RNA clearance, whereas those who normally drank heavily
but abstained from drinking before interferon treatment showed some improvement
in HCV RNA clearance (and the virus completely disappeared in 15.8 percent
of heavy drinkers who abstained before treatment) (Mochida et al. 1996).

However, this study indicated
that when HCV–infected alcoholic patients who normally drank heavily
(70 or more grams of alcohol, or at least 5.8 drinks, per day) abstained from
alcohol consumption during interferon therapy, their rate of HCV RNA clearance
was markedly lower than was the case for HCV–infected nondrinkers (see
figure 6). These results were confirmed by a recent Italian study (Tabone
et al. 2002) in which 150 patients with chronic HCV underwent interferon treatment
for 1 year after 6 months of abstinence from alcohol. (Abstinence was verified
by analyzing blood levels of a biological marker of heavy alcohol consumption
known as carbohydrate–deficient transferrin.) Although all patients
had abstained from alcohol before beginning treatment, only 9 percent of (normally)
heavy drinkers exhibited a sustained response to the interferon treatment,
compared with 20 percent of light drinkers and 33 percent of nondrinkers.
The factors that most strongly predicted a poor response to interferon treatment
were the specific type of HCV infection (patients with HCV genotype 1b were
least responsive), patients’ age, and their lifetime alcohol intake.

Figure 6
Six months after completion of a 24–week course of interferon
treatment, HCV–infected patients who were not alcoholics showed
significantly better virological and biochemical responses to therapy
than did alcoholic patients. (Response to therapy was assessed by measuring
blood levels of the virus itself [HCV RNA] and of the enzyme alanine
aminotransferase [ALT], a marker for liver inflammation.)

SOURCE: Mochida
et al. 1996.

Treatment
Recommendations

The evidence is strong
that continued heavy alcohol intake during interferon treatment adversely
affects treatment effectiveness. Further, depression, irritability, and anxiety—side
effects that occur in 20 to 30 percent of patients who receive interferon
treatment—may be especially difficult to manage for patients with a
history of alcoholism, predisposing them to begin drinking again (Zdilar et
al. 2000). Despite this risk, however, the data do not support withholding
interferon therapy for chronic HCV from patients with a history of alcoholism
or heavy drinking if they remain abstinent and have adequate psychosocial
support during treatment. Likewise, light–to–moderate drinkers
should not be excluded from HCV treatment, nor should a period of abstinence
before starting therapy be enforced in this patient population.

Directions for Future
Research

A recent National Institute
on Alcohol Abuse and Alcoholism conference (Morgan et al. 2003) identified
areas of research with the greatest potential for leading to more effective
treatment options. Conference recommendations for research within these areas
were as follows:

Clinical Studies

Determine how variations
in the amount and pattern of drinking, combined drinking and smoking,
and nutritional deficiencies affect HCV–infected patients’
risk of liver injury, disease progression, and death.

Evaluate the effectiveness
of alcohol cessation programs in patients with HCV.

Specify how alcohol
affects patients’ response to interferon treatment, including chemical
interactions and day–to–day changes in virus activity during
treatment.

HCV Virology

Determine how alcohol
affects viral replication, clearance, and persistence and the evolution
of new HCV quasi–species.

Examine whether alcohol
use leads to greater dominance of more harmful genetic variants of HCV.

Identify the effects
of alcohol on immune responses to HCV, including changes in quality, behavior,
and survival of immune cell populations both within and outside the liver.

Mechanisms
of Liver Injury

Determine what factors
activate the liver cells that deposit fibrous material at the site of
injury and cause scarring (i.e., hepatic stellate cells). These factors
may include the patient’s immune response to HCV infection, the
specific HCV genotype, and oxidative stress triggered by alcohol use.

Identify factors
(including complementary medicines) that may inhibit stellate cell activation
and fibrosis in HCV–infected patients who use alcohol.

Clarify the roles
that alcohol and HCV infection play in oxidative stress, lipid peroxidation,
and disruption of cell function.

Determine the source
of proteins, known as cytokines, that act as antibody–mediated (humoral)
messengers between liver cells, and their role in liver cell injury and
regeneration in HCV–infected patients who use alcohol.

Evaluate the effect
of alcohol and HCV infection on fatty liver and determine how steatosis
contributes to liver disease.

Characterize the
effect of human liver cells (i.e., hepatocytes) on overall human pathophysiology
in response to alcohol and HCV.

Identify genetic
factors that affect the severity of alcohol– and HCV–induced
liver disease.

Model Systems

Develop animal models
(using living animals and laboratory cell cultures) of HCV infection and
of alcoholic liver disease that reproduce disease processes found in humans.

Summary

Excessive alcohol consumption
among patients infected with chronic hepatitis C is likely to result in more
severe liver injury, promoting cirrhosis and increasing the risk for development
of liver cancer (specifically, hepatocellular carcinoma). Although the mechanisms
by which chronic hepatitis C progresses to more severe liver disease in alcoholic
patients have not been clearly established, they may include an alcohol–induced
increase in viral replication; rapid mutation of HCV, leading to greater viral
complexity; increased liver–cell death and inflammatory response; suppression
of immune responses; accumulation of fat in the liver; and accumulation of
excess iron in body tissues.

In addition to greatly
heightening HCV–infected patients’ risk of serious liver disease,
heavy drinking during antiviral (interferon) treatment has been shown to impede
patients’ responses to therapy. Abstaining from drinking before and
during treatment improves patients’ response to antiviral therapy, although
this improvement is not total. In light of these findings, alcoholic patients
should be advised to abstain from further alcohol consumption and should be
alcohol free for at least 6 months before beginning interferon therapy.

Future research should
further examine the effects of light and moderate drinking on features of
the hepatitis C virus; alcohol’s effect on virus activity and response
to treatment; patients’ immune responses to the virus; mechanisms of
fibrosis in response to HCV infection and alcohol use; and animal models of
HCV infection that may shed greater light on disease processes in humans.

Centers for Disease Control
and Prevention. Recommendations for prevention and control of hepatitis C
Virus (HCV) infection and HCV–related chronic disease. Morbidity
and Mortality Weekly Report 47:1–39, 1998.